Approximately 15% of type 2 diabetes mellitus (T2DM) patients will develop a diabetic foot ulcer (DFU). Despite several therapeutic approaches for wound treatment, approximately 15-20% of all DFUs ultimately require amputation. A major risk factor for the development of DFUs is diabetic peripheral neuropathy (DPN), which affects between 30-50% of all diabetic patients. The underlying mechanisms that cause DPN are not fully understood, and there are no FDA-approved therapies to prevent or reverse its progress. DPN is characterized by impaired metabolic and microvascular functions, which damage the endoneural capillaries that supply the peripheral nerves. Therefore understanding the diverse roles of bioenergetics and the microvasculature in the pathogenesis of DPN might facilitate the search for novel therapeutic compounds to prevent and treat DPN. Importantly, both metabolic and microvascular functions can be assessed using multinuclear MRI. Whereas phosphorus (31P) magnetic resonance (MR) can noninvasively assess skeletal muscle bioenergetics, microvascular function in muscle can be measured using post-contractile changes in blood oxygenation level dependent (BOLD) MRI signals. While typical 31P-MR approaches are limited by low sensitivity and poor spatial resolution, we have developed 31P-MRI methods that yield extensive muscle coverage and up to 30-fold increased spatial resolution compared with existing methods. This development in high-resolution 31P imaging allows us to examine focal areas of metabolic impairment, which are likely to occur in DPN. In this study we propose continued development of the 31P-MR acquisition to further improve the sensitivity of our measurements on a clinical (3T) MRI scanner and determine if our 31P-MR techniques, combined with BOLD-MRI, can i) detect presence and severity of DPN and ii) predict DFU formation. Our main working hypothesis is that multinuclear MRI will enable early detection of DPN and provide new insights into the vascular and metabolic impairments in the diabetic lower leg muscles that lead to complications, such as DFU formation. The proposed study has three specific aims: 1.) To enhance the sensitivity of 31P-MR metabolic outcomes through improved design and construction of a highly sensitive 3T dual-tuned (31P/1H) multi-channel array coil; 2) To perform a cross-sectional study and determine whether co-localized multinuclear MRI at 3T detects presence of DPN; and 3.) To perform a 2-year longitudinal study to determine if changes in multinuclear MRI measures of muscle perfusion and metabolic function at 3T indicate DPN progression and whether they can predict DFU formation. This proposal has a high likelihood of establishing multinuclear MRI as a non-invasive method for the early diagnosis and staging of DPN. It promises to enable new insights into the diverse roles of bioenergetics and microvascular factors responsible for the onset and progression of the disease. Multinuclear MRI might emerge as a key imaging approach to guide the diagnosis and therapy of DPN.